U.S. patent number 5,677,355 [Application Number 08/475,218] was granted by the patent office on 1997-10-14 for continuous open-cell polymeric foams containing living cells.
This patent grant is currently assigned to Smith & Nephew, Inc.. Invention is credited to Susan L. Roweton, Shalaby W. Shalaby.
United States Patent |
5,677,355 |
Shalaby , et al. |
October 14, 1997 |
**Please see images for:
( Certificate of Correction ) ** |
Continuous open-cell polymeric foams containing living cells
Abstract
A polymeric foam with continuous, open-cell pores containing
living cells suitable for medical applications and methods for
preparing these foams. The microporous foams are of controlled pore
size that may be utilized in a variety of applications. In general,
the foams are characterized in that the pores are continuous and
open-celled. In preparing the foams, an organic polymer is melted
and combined with a selected solid crystalline fugitive compound,
that melts above about 25.degree. C. and/or that sublimates at
above about 25.degree. C. or can be extracted, to produce a
substantially isotropic solution. The solution is cooled under
controlled conditions to produce a foam precursor containing the
solidified fugitive composition dispersed through a matrix of the
organic polymer. Crystals of fugitive composition are then removed
by solvent extraction and/or sublimation, or a like process to
produce microcellular foams having a continuous, open-cell
structure. After removing the fugitive composition, living cells
capable of producing biologically active products are added to the
pores to produce a foam containing living cells.
Inventors: |
Shalaby; Shalaby W. (Anderson,
SC), Roweton; Susan L. (Clemson, SC) |
Assignee: |
Smith & Nephew, Inc.
(Memphis, TN)
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Family
ID: |
22309287 |
Appl.
No.: |
08/475,218 |
Filed: |
June 7, 1995 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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106064 |
Aug 13, 1993 |
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Current U.S.
Class: |
521/61; 424/486;
424/93.1; 521/102; 521/149; 521/182; 521/49; 521/63; 521/84.1 |
Current CPC
Class: |
A61K
9/122 (20130101); A61L 27/16 (20130101); A61L
27/18 (20130101); A61L 27/38 (20130101); A61L
27/3839 (20130101); A61L 27/3847 (20130101); A61L
27/3852 (20130101); A61L 27/56 (20130101); B01D
67/003 (20130101); B01D 69/141 (20130101); B29C
67/202 (20130101); C08J 9/26 (20130101); A61L
27/18 (20130101); A61L 27/54 (20130101); A61L
27/56 (20130101); A61L 27/58 (20130101); A61L
27/38 (20130101); C08L 67/04 (20130101); A61L
27/18 (20130101); A61L 27/38 (20130101); A61L
27/58 (20130101); A61L 27/56 (20130101); A61L
27/54 (20130101); C08L 67/04 (20130101); A61L
27/16 (20130101); C08L 23/00 (20130101); A61L
27/18 (20130101); C08L 67/04 (20130101); A61L
27/18 (20130101); C08L 77/00 (20130101); A61L
27/18 (20130101); C08L 71/12 (20130101); C08J
2201/042 (20130101); C08J 2205/05 (20130101); B01D
2323/21 (20130101); B01D 2325/48 (20130101); Y10T
428/31504 (20150401); Y10T 428/249958 (20150401); Y10T
428/31931 (20150401); Y10T 428/31725 (20150401); Y10T
428/31938 (20150401) |
Current International
Class: |
A61K
9/12 (20060101); A61L 27/16 (20060101); A61L
27/38 (20060101); A61L 27/00 (20060101); A61L
27/56 (20060101); A61L 27/18 (20060101); B01D
69/00 (20060101); B01D 67/00 (20060101); B01D
69/14 (20060101); B29C 67/20 (20060101); C08J
9/00 (20060101); C08J 9/26 (20060101); C08J
009/26 (); A61K 009/14 () |
Field of
Search: |
;521/61,63,84.1,102,149,182,189 ;264/41,49 ;424/93.1,486 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Aubert, J.H. and Sylwester, A.P., "Microcellular Foams? For What?,"
Chemtech, 1991, 21, pp. 234-238 (1991), American Chemical Society.
.
Aubert, J.H. and Sylwester, A.P., "Microcellular Foams? Here's
How!," Chemtech, 1991, 21, pp. 290-295 (1991), American Chemical
Society. .
Aubert, J.H. and Clough, R.L., "Low-density, microcellular
polystyrene foams," Sandia National Laboratories (Feb. 5, 1985).
.
Aubert, J., Sylwester, A., and Rand, P., "Microcellular Polymer
Foams for Controlled Release and as Biomaterials," Sandia National
Laboratories, pp. 447-448 (1991). .
Renschler, C.L. and Sylwester, A.P., "Novel Forms of Carbon from
Poly(acrylonitrile): Films and Foams," Materials Science Forum,
vol. 52 & 53 (1989), pp. 301-322. .
Roweton, S., "High Melting Solid Media for Production of
Microporous Polymeric Foams," Patent Application Disclosure,
Revised Aug. 4, 1993. .
Roweton, S., "A New Approach to the Formation of Tailored
Microcellular Foams and Microtextured Surfaces of Absorbable and
Non-Absorbable Thermoplastic Biomaterials," Master of Science
Thesis presented to Graduate School of Clemson University (Dec.
1993)..
|
Primary Examiner: Cooney, Jr.; John M.
Attorney, Agent or Firm: Pravel, Hewitt, Kimball &
Krieger
Parent Case Text
This is a division of application Ser. No. 08/106,064 filed Aug.
13, 1993 which is now abandoned.
Claims
What is claimed is:
1. A foam comprising:
an organic polymeric matrix with continuous, open-cell pores
dispersed therein; and
living cells producing at least one product, the living cells
contained in the pores,
the foams produced by a process comprising the steps of:
combining an organic polymer with a fugitive composition that is a
solid cristalline material that melts above 25.degree. C.
co-melting and co-dissolving the fugitive composition with the
polymer to produce a substantially isotropic solution;
solidifying the isotropic solution to produce a foam precursor
containing crystals of the fugitive composition;
removing the crystals of the fugitive composition from the foam
precursor to produce a continuous, open-cell foam; and
adding selected living cells to the foam for inhabiting the pores
and producing at least one product.
2. The foam of claim 1, wherein the foam is of a predetermined
shape suitable for implantation into a living skeleton for
repairing a wound and the at least one product includes a bone
morphogenic protein.
3. The foam of claim 1, wherein the foam is adapted for
implantation into a living body and the cells produce at least one
biologically active compound that promotes reconstruction of
damaged body tissue.
4. The foam of claim 1, wherein the cells utilize a nutrient medium
to produce the product.
5. The foam of claim 4, wherein the foam is in the form of hollow
fibers.
6. The foam of claim 2, wherein the organic polymer is a
bioabsorbable polymer.
7. The foam of claim 3, wherein the organic polymer is a
bioabsorbable polymer.
8. The foam of claim 6, wherein the bioabsorbable polymer is
selected from the group consisting of polylactic acid, polyglycolic
acid, polyalkylene oxalates, poly-p-dioxane, polyanhydrides,
polymorpholinediones, polycaprolactone, and copolymers thereof.
9. The foam of claim 7, wherein the bioabsorbable polymer is
selected from the group consisting of polylactic acid, polyglycolic
acid, polyalkylene oxalates, poly-p-dioxane, polyanhydrides,
polymorpholinediones, polycaprolactone, and copolymers thereof.
10. The foam of claim 2, wherein the foam is shaped as a prosthetic
implant.
11. The foam of claim 3, wherein the foam is shaped as a prosthetic
implant.
12. The foam of claim 1, wherein the pore diameter is in the range
of about 1 micron to about 400 microns.
13. The foam of claim 1, wherein the living cells are adhered to
walls of the pores.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to microporous thermoplastic foams and
microtextured films and methods for preparing these foams and
films. More specifically, the invention provides a method for
producing foams with controlled pore size, chemical reactivity and
mechanical properties, as well as microtextured surfaces with
modulated microroughness, lyophilicity, and chemical reactivity
that may be utilized in a variety of applications, including drug
delivery systems, constructs for bone and cartilage regeneration,
constructs for organ generation, filters for protein fractionation,
matrices for gas and fluid filtration, templates for
three-dimensional cell cultures, bioreactor substrate material,
constructs containing immobilized chemical and biological reagents
for use in continuous chemical and biochemical processing, and the
like.
2. Description of the Related Art
It is expected that there are many potential biomedical
applications for microcellular foams although not necessarily
disclosed in the prior art. Among the potential uses are, use as
timed-release drug delivery systems, neural regeneration pathways,
templates for skin generation/regeneration, vascular replacements,
and artificial bone templates. Specific areas of immediate
biomedical significance include use of absorbable microcellular
foams for bone and cartilage regeneration applications as well as
the use of microcellular foams for organ generation, components of
bioreactor cartridges, such as those useful for the production of
growth factors, microcellular filters for protein fractionation,
microcellular matrices for gas and fluid filtration, and
microcellular constructs containing immobilized chemical and
biological reagents for use in continuous chemical and biochemical
processing, some of these applications are discussed in the patent
literature.
For instance, U.S. Pat. Nos. 4,902,456 and 4,906,377 discuss the
manufacture of fluorocarbon porous films from
poly(tetrafluoroethylene-co-perfluoroalkyl vinyl ether) (PFA) or
poly(tetrafluoroethylene-co-hexafluoropropylene) (FEP). The porous
films are permeable to both liquids and gases and can be used as
filtration media. In producing the films, a mixture is formed that
comprises between about 10 to about 35 wt. % FEP or PFA polymer
with the remainder being a solvent (porogen) chlorotrifluorethylene
oligomer which permits liquid--liquid phase separation upon cooling
from elevated temperature and subsequently solidification of the
polymer. The mixture is heated and extruded to form a film or
hollow fibers which are then quenched to effect phase separation of
the fluorocarbon polymer from the solvent. The extrudate is
quenched by passing it over a chill roller which cools the
extrudate to a temperature that causes microphase separation of
polymer and solvent. The solvent is separated from the polymer by
extraction and the resultant microporous polymeric membrane is
dried under restraint in order to minimize or prevent membrane
shrinkage and collapse.
U.S. Pat. No. 4,603,076 relates to hydrophilic flexible foams that
are said to be particularly suited for use in external biomedical
applications. The polyurethane films are produced by blowing a
methylene diphenyl diisocyanate (MDI) prepolymer with a
substantially non-aqueous blowing agent, such as pressurized air.
The prepolymer is then polymerized with polyoxyethylene polyol
having at least two hydroxyl equivalents per mole. The hydrophilic
foam may be extruded, knife coated, or cast into sheets.
Likewise, U.S. Pat. No. 5,071,704 relates to specific foams into
which a reservoir layer maybe incorporated for allowing controlled
release of vapors or liquids of an active compound into the
surrounding environment. This is accomplished by incorporating a
diffusion rate-limiting membrane layer, into a laminate of the
foam, which controls the rate at which the active compound diffuses
to the surface of the laminate and vaporizes or dissolves into the
environment.
U.S. Pat. No. 5,098,621 relates to flexible foam substrates for
selectively releasing and dispensing active ingredients. The
composite material includes an open foam substrate containing
particles of micropackaged active ingredient liquids or solids,
formed with frangible containment walls, for breaking and releasing
active ingredients in response to a defined level of stress.
Whereas the above patents indicate methods for making foams,
microcellular foams made from biomedically significant polymers are
of particular interest. Further, production of polymeric
microporous foams having continuous cellular structures has not
been exploited to any great extent. Microcellular foams have been
produced using various materials and processes, but these foams
cannot be produced from biomedically useful polymers using the two
traditional methods: low temperature freeze drying and salt
leaching, or the more recent technique, thermally induced phase
separation (TIPS). Salt leaching has several limitations including
the factor that it is often difficult to form small micropores with
salt and it requires a high salt loading to achieve interpore
channeling to produce continuous microporous foams. Further, there
is a limited availability of solvents for polymers intended for
biomedical use. Freeze drying also has its limitations.
Specifically, there is a limited availability of crystallizable
solvents that can be sublimed at the low temperatures
characteristic of the freeze drying process. Further, the freeze
drying process is a batch process which imposes limitations in
terms of the size and shape of the foam produced.
TIPS, in concert with low-temperature freeze-drying technology, has
been used to produce microcellular foams made of dextran,
cellulose, and polystyrene. Limitations associated with available
materials and solvents have generally restricted the growth of TIPS
foam formation technology. In the TIPS process, the pore formation
is preceded by a liquid--liquid, liquid-solid, or solid-liquid
phase phase separation that is difficult to control. Further, the
TIPS process requires solidifying the solvent-polymer mixture with
rapid cryogenic quenching. This type of quenching presents an
obstacle to large scale manufacturing processes.
Production of microcellular foams with controlled chemical and
mechanical properties and morphology would facilitate the use of
biologically safe polymers for the production of microcellular
foams for biomedical applications. The growing demand for polymeric
microcellular forms in several areas of advanced technology
represent an urgent need for developing a method for converting
non-bioabsorbable and bioabsorbable polymers, which cannot be
processed in a traditional manner, to microcellular foams.
There exists a need for a continuous, open-cell microcellular foam,
and a process for producing such a foam, on a typical manufacturing
scale, from organic polymers suitable for biomedical applications,
without need for complex new equipment to make the foams. Further,
the process should be readily applicable to a broad range of
thermoplastic polymers which can be absorbable or non-absorbable.
Representative non-absorbable polymers include, but are not limited
to, polyamides, aromatic polyesters, and polyolefins, while the
absorbable type of polymers can be based totally or partially on
polymers such as polylactic acid, polyglycolic acid, polyalkylene
oxalate, polydioxanone, and polyanhydride. Further, the process
should allow some measure of control of the size of the open-cell
pores or voids so that foams may be custom tailored for particular
applications, such as timed-release drug delivery systems,
constructs for regeneration of bone, cartilage, and a multiplicity
of soft tissues (including skin and liver) constructs for organ
generation, filters for protein fractionation, matrices for gas and
fluid filtration, constructs for use in bioreactor cartridges used
for continuous chemical and biochemical processing, and the like.
The inner and outer microporous cell surfaces can be chemically
activated to allow the creation of chemically active
functionalities which can be used to bind biologically active
agents ionically or covalently.
SUMMARY OF THE INVENTION
The invention provides microcellular foams produced by a process
that allows controlled formation of continuous open-cell pores or
voids using a broad range of polymeric thermoplastic precursors and
following processing schemes that are adaptable to a number of
large manufacturing schemes. The foams have a matrix of an organic
polymer with continuous, open-cell pores dispersed throughout the
matrix, and are produced by a process that requires the blending of
molten polymer with a relatively low molecular weight fugitive
compound that is a crystalline solid that melts at temperatures
above about 25.degree. C. and/or can be sublimed and extracted in a
broad range of temperatures above about 25.degree. C.
In producing the microporous foams, an organic polymer is co-melted
with the solid, crystalline, fugitive organic compound to produce a
substantially isotropic solution. The isotropic solution is
solidified by quenching, either by conventional cryogenic
techniques or by ambient cooling, using a water or air as a
convection medium, to produce a foam precursor. In most cases, the
foam precursor is a matrix of 25 the organic polymer with a
fugitive compound dispersed as a microcrystalline solid therein and
a few cases as an intermolecular moiety with no distinct
crystalline lattice. The fugitive compound can be removed by
several techniques, depending upon the specific composition.
Typically, the crystals are removed by leaching with a solvent or
sublimation through heating under vacuum. The resultant continuous,
open-cell foams are microporous and suitable for a variety of
applications, among which are medical applications.
The inventive microporous foams can be made in a variety of shapes,
depending upon requirements. For example, microporous foam in the
form of hollow fibers, catheters, films or sheets, can be produced
by extrusion of the molten, substantially isotropic solution that
contains the organic polymer and the fugitive composition. The
extrudate, consisting of a foam precursor, may then be treated to
remove the fugitive composition either by leaching with a solvent,
and/or sublimation of the composition. Alternatively, the foam
precursor may be in the core of a fiber extrudate so that upon
removal of the fugitive compound, an extrudate, with a hollow core
and solid sheath is obtained.
Different forms of filamentous foams having a high surface area to
volume ratio, may be used to fabricate bioreactors for producing a
range of biological products. For example, living cells maybe
cultured on the extensive surface area provided by these hollow
fibers or tubes and, since the foam is of an open-cell nature,
nutrients may readily be supplied to the cells and products readily
removed for further processing and use. The structure of the foam
also allows the facile transport of waste products.
Further, the open-cell foams may be fabricated of a bioabsorbable
polymer, so that these may be implanted into a living body with or
without the incorporation of certain bioactive agents, such as
growth factors, for tissue regeneration purposes. Thus, the
implanted bioabsorbable foam may be shaped and fitted as a
prosthetic implant or construct to repair skeletal or soft tissues
so that as bone or specific soft tissue grows into the
bioabsorbable foam implant, the implant gradually absorbs until the
skeletal or soft tissue structure is repaired and the implant
completely absorbed. Specifically for bone generation, the pores of
the bioabsorbable construct may be doped with bone morphogenic
protein, or cells producing such proteins and other desirable
biologically active substances, to promote healing and bone growth.
Likewise, constructs may be fabricated for use in repairing
ligament or soft tissue of living bodies utilizing bioabsorbable
polymeric matrices, with suitable pharmacologically active and/or
biologically active materials or cells producing such active
materials, in the pores of the construct.
The foams which can be processed in the precursor stage by
extrusion, casting or other methods for production of shaped
articles, due to the custom tailored nature of the pores, are also
useful as devices for the timed delivery of drugs, for instance
transdermally. Thus, given the diffusion kinetics of a certain
medicament, a foam may be custom tailored with a particular pore
size which can be doped with the medicament to release the
medicament to the patient at a controlled, desired rate.
The foam-precursor technology that is the subject of this invention
can be used on a limited basis to create a thin microporous layer
on the outer-most boundaries or surfaces of polymeric articles by
dipping such articles in the fugitive composition medium to
co-dissolve with the polymer comprising the base of the polymeric
articles. Depending upon the dipping time and temperature, the
thickness of the foamy parts can be modulated. This thin
microporous layer can be from one to a few pores in thickness and
can provide a means for surface microtexturing. Surfaces with
variable foam depths can be achieved on high melting and/or low
solubility polymers, such as polyetheretherketone (PEEK) and ultra
high molecular weight polyethylene (UHMWPE). Orthopedic implants
with porous outermost components facilitates bone-ingrowth into the
implant and hence enhances development of mechanical stability. The
performance of implants with microporous or textured surfaces can
be further improved by chemical activation of the inner and outer
cell walls by a process such as phophonylation. An alternate method
to creating the desired surface morphology is obtained using the
isotropic solution as a dipping medium, instead of the fugitive
composition.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention provides microcellular foams having a continuous,
open-cell structure and a process for preparing such foams. The
invention process permits a degree of control over the range of
pore sizes so that the foams may be custom-tailored for specific
applications. The applications include, but are not limited to,
timed-release drug delivery systems, constructs for hone, cartilage
and soft tissue regeneration, organ generation, filters for protein
fractionation, microcellular matrices for gas and fluid filtration,
bioreactors containing immobilized chemical and biological reagents
for use in continuous chemical and biochemical processing to
produce useful products.
Conventional foams, produced by traditional methods of foam
formation, have voids or pores ranging from 50 to 100 microns in
diameter. By some definitions, microcellular foams are those
containing cells less than 50 microns in diameter. However, in the
specification and claims, materials referred to as microcellular
foams are those foams containing voids or pores of varying
geometries, that are suitable for biomedical applications. Such
foams preferably contain pores or voids with dimensions of from
about 1 to about 400 microns, most preferably from about 5 to about
200 microns.
Foams, according to the invention, may be made from suitable
organic polymeric materials, including the bioabsorbable and
non-bioabsorbable thermoplastic polymers. The non-bioabsorbable
medically significant polymers include the polyamides, polyesters,
and polyolefins. The bioahsorbable polymers include
poly(dioxanone), polyglycolic acid, polylactic acid, polyalkylene
oxalates, polyanhydrides and copolymers thereof.
Depending upon the polymer selected and the size and distribution
of voids or pores within the foam, the foams may range in
mechanical properties from flexible to semi-flexible to rigid.
Thus, foams according to the invention may be tailored for specific
uses by judicious selection of polymer, and void or pore size,
depending upon the intended use of the foam construct.
In order to prepare the foams according to the invention, a
"fugitive composition" is required. These fugitive compositions are
solid crystalline compositions that have molecular weights of less
than about 300 daltons and that are able to form a substantially
isotropic solution when combined with the molten polymer that will
form the substrate of the foam. Upon cooling of the substantially
isotropic polymer-fugitive compound solution, the fugitive compound
should separate from the polymer by crystallizing or forming
inter-macromolecular entities. This is realized through
crystallization-induced microphase separation (CIMS). These
crystals or entities may then be subsequently removed from the
solidified polymer to produce voids or pores in the spaces they
previously occupied. The preferred fugitive compound are those
solid, crystalline compositions that melt at temperatures above
about 25.degree. C.; and those crystalline solid compositions that
sublime at temperatures above about 25.degree. C. and that may also
be extracted with solvents. Examples of suitable fugitive compounds
include salicylic acid, naphthalene, phenanthrene, anthracene, and
tetramethylene sulfone.
Since the foams (including thin, foamy upper-most layers or
surfaces) of the invention are produced using a solid that
crystallizes, the size of the voids or pores may be controlled by
controlling the relative rates of crystal growth and nucleation.
Thus, for example, all other things being equal, if it is desired
to produce smaller pores, then conditions must be selected to favor
nucleation over crystal growth. This will ensure the presence of a
relatively larger number of relatively small crystals dispersed
throughout the solidified polymer matrix (the foam precursor). The
crystals may then be removed from the foam precursor, either by (1)
sublimation under suitable heat and/or vacuum, or (2) extraction
with a solvent under suitable heat, (3) or both; to produce a foam
containing small pores. If, on the other hand, a foam with larger
pores or voids is desired, then process conditions should be
modified to favor crystallization over nucleation. Under these
circumstances, fewer crystal nuclei will be produced and the
fugitive composition will crystalize into relatively fewer large
crystals in a foam precursor. Upon removing these crystals from the
foam precursor, relatively larger voids or pores will be produced
in the open-cell foam.
In the process for producing the foams of the invention, the
selected polymer is typically heated to above its melting
temperature, to form a polymeric melt. This melt is combined with
the selected fugitive composition that melts at above 25.degree. C.
of that sublimates at above about 25.degree. C. The combination of
molten polymer and fugitive compound produces a substantially
isotropic solution. This solution may be solidified to produce a
foam precursor including a solid polymeric matrix with crystals of
the fugitive material dispersed throughout the matrix. As explained
above, the relative size of the crystals may be determined by
judicious selection of processing conditions. It is important to
note that the quenching of the substantially isotropic solution to
produce the foam precursor is not necessarily conventional
cryogenic quenching wherein the solution is chilled by liquid
nitrogen or dry ice (frozen carbon dioxide). Instead, the quenching
step may be carried out by convective cooling with air or cooling
in a water bath. This flexibility of the process of the invention
is particularly important in that it allows the extruding of the
substantially isotropic solution without need for cryogenic cooling
of the extrudate as it exits the extrusion dye. Similarly, the
casting of the foam precursors can be simplified.
Once the foam precursor is produced, regardless of whether by
conventional cryogenic quenching or by water or air cooling, the
fugitive composition, now finely dispersed throughout the foam
precursor, must be removed in order to form the continuous,
open-cell pores characteristic of the foams of the invention. These
fugitive composition crystals may be removed by leaching with a
solvent for the crystals, that is not a solvent for the polymer
matrix. Thus, an important consideration in selecting the solvent
is that it should be soluble in a solvent that is not a solvent for
the organic polymer from which the foam will be made.
Alternatively, if the solid crystalline material is one that
sublimates at a temperature above 25.degree. C., then it is
important to select a polymer that retains its physical integrity
by having a melting point (Tm) and/or glass transition temperature
(Tg) well above the prevailing sublimation temperature and does not
degrade at around the sublimation temperature of the solid fugitive
compound.
The proportion of organic polymer and fugitive composition that
must be mixed to produce a foam will vary depending upon the
percentage of voids and the size range of the voids desired within
the foam. Thus, if a large percentage voids is required, then a
relatively larger proportion of the fugitive compound is added to
the organic polymer. Minimum pore dimensions can be achieved with
fugitive compositions proportions that allow only formation of
inter-macromolecular entities. Typically, however, in order to
produce a foam for biomedical applications, foams must have a
percent voids ranging from about 25 to about 90 percent, more
typically 50 to 80 percent, by volume. To produce such foams, from
about 5 to about 90 wt. % fugitive composition should be added to
the polymer; preferably, from about 10 to about 75 wt. % fugitive
composition, based upon the combined weights of the polymer and
fugitive composition and on the assumption that the fugitive
composition and polymer have approximately similar densities.
It is known that certain polymeric materials do not readily form a
solution with common organic solvents to create a porous or
"foam-like" surface on the polymeric substrates. These are referred
to as "polymers not readily soluble in conventional solvents."
Among these polymeric materials are polyether-etherketone (PEEK),
certain aromatic liquid crystalline polymides, polyesters and the
like. In order to create a microporous morphology in the outer-most
layers as surface layers, or microtexture the surfaces of
substrates, especially films, of polymeric materials, according to
the invention the polymeric material is subjected to hot, molten
fugitive composition for a period of time sufficient to co-dissolve
the surface of the film (or any other shaped articles) to a desired
extent. Thereafter, the substrate is cooled and the solid
crystalline material is removed by sublimation and/or extraction
with a solvent, as explained above. As a result, the surface of the
substrate exhibits continuous microporosity or is microtextured
with pores or voids.
The invention also provides polymeric substrates with thin,
continuously porous or microtextured surfaces. The microtexturing
process according to the invention produces surfaces that have a
porous texture with pore sizes ranging from less than about 1.0
microns up to about 20 microns in diameter in the surface of
organic polymeric films and other substrates. In a broader sense,
implants with modified surfaces and immediate subsurface
micromorphology can be prepared by one of two methods. In a first
method, the implant is coated with a thin layer of the isotropic
solution containing both the desired polymer co-dissolved with the
fugitive composition. The coating is then quenched, by a suitable
process, to produce a thin layer of foam precursor that adheres to
the surface of the implant. The fugitive composition is then
removed from the foam precursor layer by solvent extraction,
sublimation, or combination of these processes. The result is an
implant with a thin microporous foam coating that allows tissue
ingrowth so that the implant is better anchored in the body. The
pores of the foam layer may be filled with pharmacologically or
biologically active materials to facilitate healing, reduce risk of
infection, and promote tissue growth.
In the event that the implant is fabricated from a polymeric
composition or a polymeric composite, then the implant may be
microtextured by coating with a medium containing a fugitive
composition. The coated implant is then subjected to conditions
that will cause the polymeric surface of the implant to co-dissolve
or co-melt with the fugitive composition. Thus, the outer surface
of the composite or polymer implant is converted into a foam
precursor. This foam precursor can then be treated by solvent
extraction or sublimation or both to remove the fugitive
composition to produce a microtextured or microporous surface. The
invention also provides bi-component constructs that include a foam
core with a solid polymeric skin or surface layer surrounding the
core. Such bicomponent constructs may be readily produced by
several methods including, for instance, subjecting foam filaments
produced, as described above, to heat to cause the outer surface to
melt and flow and thereby form an outer skin. Alternatively,
filaments maybe extruded a lower melting point polymeric sheet to
facilitate subsequent melting of the outer layer to form the
polymeric skin.
When the foams of the invention are intended for implantation into
a living patient, then they maybe supplied with suitable
medicaments, including growth factors, pharmacologically active
compounds, and biologically active compounds or living cells
capable of producing such biologically active compounds. The
medicaments include anti-bacterial agents, anti-inflammatory
agents, and the like. The biologically active agents include for
example, insulin, insulin-like growth factor (IGF), fibroblast
growth factor (FGF), epidermal growth factor (EGF),
platelet-derived growth factor (PDGF), and the like. As a general
principal, the foams may be doped with any agent or living cell
capable of producing that agent in order to enhance the
effectiveness of the foam in its intended function in the body. In
one embodiment, the foams may be doped with a slightly soluble
pharmaceutical product that may be added with the fugitive
composition. The resultant foam precursor produced may be subjected
to steps for removing the fugitive composition that result in
retaining the pharmaceutical product in the voids or pores of the
foam. Thus for instance, if the pharmaceutical product has higher
thermal stability than a fugitive composition that is able to
sublimate, then removal of the fugitive composition by sublimation
will permit the retention of the medicament in the pores of the
foam.
The following examples illustrate certain embodiments of the
invention and do not in any way limit the scope of the invention as
described above and claimed hereafter.
EXAMPLES
Example 1
Nylon 6 Microporous Foam Using Salicylic Acid As the Fugitive
Composition
Nylon 6 fibers were heated with solid salicylic acid to form a 10%
(by weight) Nylon 6 solution. The solution was heated close to, but
not exceeding 230.degree. C., in an inert atmosphere to produce an
isotropic solution. The processing vessel was then quenched in
25.degree. C. water bath. The solid foam precursor obtained was
then heated to 78.degree. C. while vacuum was applied to remove the
salicylic acid by sublimation.
Characterization by light microscopy revealed a porous, foam
morphology. Continuous porosity was verified by monitoring the fast
transport of an aqueous dye solution through the foam.
Example 2
Nylon 12 Microporous Foam Using Salicylic Acid as the Fugitive
Composition
Solid Nylon 12 pellets were heated with solid salicylic acid to
form a 30% (by weight) isotropic solution while using mechanical
stirring. The solution was heated to about 190.degree. C. in an
inert atmosphere and the processing vessel was then quenched in
liquid nitrogen. The solid foam precursor obtained was washed with
chloroform to remove the salicylic acid.
Characterization of the Nylon 12 foam was accomplished using
scanning electron microscopy (SEM) and revealed a pore size of 50
to 100 microns. Continuous porosity was verified using the
dye-transport method described in Example 1.
Example 3
Nylon 12 Microporous Foam Using Naphthalene
Solid Nylon 12 pellets were heated with solid naphthalene to form a
30% (by weight) isotropic solution while using mechanical stirring.
The solution was heated to about 190.degree. C. in an inert
atmosphere and the vessel was then quenched in liquid nitrogen. The
solid foam precursor obtained was washed with methanol which was
cooled in liquid nitrogen to remove the naphthalene.
Characterization of the Nylon 12 form was accomplished using SEM
and revealed a pore size of 30 to 50 microns. The dye transport
method was used to verify the foam continuous porosity.
Example 4
Polyethylene Microporous Foam Using Naphthalene
Solid, high-density polyethylene pellets were heated with solid
naphthalene to form a 30% (by weight) isotropic solution while
applying mechanical stirring. The solution was heated to about
150.degree. C. in an inert atmosphere and the vessel was then
quenched in liquid nitrogen. The solid foam precursor obtained was
washed with chloroform to remove the naphthalene.
Characterization of the polyethylene foam was accomplished using
SEM and BET surface area analysis. The polyethylene foam was found
to have pores ranging from 5 to 50 microns in diameter and a
surface area of 2.3 square meters/gram. Continuous microporosity
was verified using the dye transport method.
Example 5
Polypropylene Microporous Foam Using Naphthalene
Solid isotactic polypropylene pellets were heated with solid
naphthalene to form a 20% (by weight) isotactic solution while
applying mechanical stirring. The solution was heated to about
170.degree. C. in an inert atmosphere and the processing vessel was
then quenched in liquid nitrogen. The solid foam precursor obtained
was washed with chloroform to remove the naphthalene.
Characterization of the polyethylene foam was accomplished using
SEM and revealed pores ranging from i to 50 microns in diameter.
Continuous porosity was verified using the dye transport
method.
Example 6
Polycaprolactone Microporous Foam Using Naphthalene
Solid polycaprolactone (PCL) pellets were heated with solid
naphthalene to form 20%, (by weight) isotropic solutions while
applying mechanical stirring. The solutions were heated close to,
but not exceeding, 140.degree. C. in an inert atmosphere and the
processing vessel was then quenched in liquid nitrogen. The solid
foam precursor obtained was washed with hexane to remove the
naphthalene.
Characterization of the polycaprolactone foams were accomplished
using SEM and revealed pore sizes of 5 to 50 microns. Continuous
porosity was verified using the dye transport method. Upon
repeating this process, using 10, 20, 30 and 40 weight percent PCL
to form foam precursors by casting into a precooled metallic mold,
foams were obtained having pure porosity of 50 to 200.mu. depending
on composition.
Example 7
Nylon 6 Microporous Foam Using Tetramethylene Sulfone
Solid Nylon 6 pellets were heated with tetramethylene sulfone to
form a 20% (by weight) isotropic solution while applying mechanical
stirring. The solution was heated to about 250.degree. C. in an
inert atmosphere and the process vessel was then quenched in liquid
nitrogen. The solid foam precursor obtained was washed with
methanol to remove the tetramethylene sulfone. Continuous porosity
was verified using the dye transfer method.
Characterization of the nylon 6 foam was accomplished using SEM and
revealed a pore size of 2 to 5 microns.
Example 8
Absorbable Microporous Foam Using Naphthalene
The absorbable copolyester of this example was prepared by
catalyzed polycondensation of 75/25 (molar ratio) of diemthyl
terephthalate/diethyl oxalate and 1.2 molar excess of trimethylene
glycol in the presence of about 0.05 percent (by mole) stannous
octoate as a catalyst. The polymerization was conducted in two
stages. The first, the prepolymerization stage, was conducted at a
temperature of 150.degree.-180.degree. C. under nitrogen at ambient
pressure for about 6 hours. The second stage, post polymerization,
was conducted under reduced pressure (less than 1 mmHg) at
180.degree.-210.degree. C. for about 8 hours. The resulting polymer
was cooled, ground, and dried before use. The polymer exhibited an
inherent viscosity (in CHCl.sub.3 at 30.degree. C.) of about 1.0
and a Tm of about 127.degree. C.
Solid synthetic absorbable polyester was heated with naphthalene to
form a 20% (by weight) isotropic solution while applying mechanical
stirring. The solution was heated to about 230.degree. C. in an
inert atmosphere and the processing vessel was then quenched in
liquid nitrogen. The solid foam precursor obtained was washed with
n-hexane to remove the naphthalene. The purified foam exhibited the
same inherent viscosity as that of the starting polymer.
Characterization of this absorbable polyester foam was accomplished
by SEM.
Example 9
Absorbable Microporous Copolycaprolactone Foam Using
Naphthalene
A solid absorbable copolycaprolactone (90/10 Caprolactone/Glycolide
copolymer) was heated with naphthalene to form a 20% (by weight)
isotropic solution while applying mechanical stirring. The solution
was heated up to 120.degree. C. in an inert atmosphere and the
processing vessel was then quenched in liquid nitrogen. The solid
foam precursor obtained was washed with n-hexane to remove the
naphthalene. The inherent viscosity (in CHCl.sub.3 @30.degree. C.)
of the foam was the same as that of the starting polymer (about
1.0).)
Characterization of this absorbable foam was accomplished using SEM
and indicated a pore size of 1-150 microns. The continuous porosity
was verified using the dye transport method.
Example 10
Absorbable Microporous 95/5 Copolycaprolatone Foam Using
Naphthalene
A solid synthetic absorbable polyester (95/5 Caprolactone/Glycolide
copolymer) was heated with naphthalene to form a 20% (by weight)
isotropic solution while applying mechanical stirring. The solution
was heated up to 110.degree. C. in an inert atmosphere and the
processing vessel was then quenched in liquid nitrogen. The solid
foam precursor obtained was washed with n-hexane to remove the
naphthalene. The purified foam exhibited the same inherent
viscosity (in CHCl.sub.3 @30.degree. C.) as the starting polymer
(about 0.8).
Characterization of the absorbable polyester foam was accomplished
using SEM and indicated a pore size of 1-200 .mu.m. The continuous
porosity was verified by the dye diffusion method.
Example 11
Texturing of PEEK (Poly(ether-ether ketone) Film Using
Naphthalene
A PEEK 10 mil-thick film sample (STABAR k200 manufactured by
I.C.I.) was heated with naphthalene in an inert atmosphere for 2.5
hours at a temperature between 225.degree. and 250.degree. C. The
treated film was removed and allowed to air cool at room
temperature. The solid naphthalene was removed from the "surface"
foam precursor using n-hexane after soaking for about 3 days.
Characterization of the resultant film surface was accomplished
using SEM. A porous surface was evident with pore size diameters as
small as 1 micron. The depth of the microporous layer was about
2-10 .mu.m.
Example 12
Texturing of PEEK Film Using Salicylic Acid
A 10 mil thick PEEK film (STABAR K200) was heated with salicylic
acid in an inert atmosphere for approximately 2 hours at a
temperature of approximately 240.degree. C. After air cooling the
isolated film at room temperature, the solid salicylic acid was
removed from the "surface" foam precursor using methanol after
soaking for about 3 days.
Characterization of the resultant film surface was accomplished
using SEM. A porous surface was evident with pore size diameters at
or below 1 micron. The depth of the microporous layer was about
5-10 .mu.m.
Example 13
Texturing of a Solid PEEK Coupon
A solid PEEK coupon was placed in liquid anthracene and maintained
in an inert atmosphere for 3 hours at a temperature of
approximately 260.degree. C. After isolating and air cooling the
polymer at room temperature, the solid anthracene was removed from
the foam precursor obtained with hexane.
Characterization of the resultant sample surface was accomplished
using SEM. A porous surface was evident with pore size diameters
ranging from 1 to 50 micron. The depth of the microporous layer was
shown to be about 20-200 .mu.m.
Example 14
Extrusion of Microporous Polycaprolactone (PCL) Foam Fibers
Solid PCL was heated with naphthalene to form a 40% (by weight)
isotropic solution while applying mechanical stirring. The solution
was heated up to 145.degree. C. in an inert atmosphere and the
processing vessel was then quenched in liquid nitrogen. The
co-solidified PCL/naphthalene foam precursor was then melt extruded
at about 100.degree. C. using a capillary equipped with a 40 mil
die. The resulting filaments of foam precursor were air cooled and
then washed with n-hexane to remove the naphthalene and produce PCL
foam fibers. The inherent viscosity of the purified filaments was
the same as that of the starting polymer (about 2.2 in CHCl.sub.3
@30.degree. C.).
Characterization of the PCL foam fibers was accomplished using SEM
to ascertain their microporosity. The pore size ranged from 1-5
.mu.m.
Although the invention has been described with reference to its
preferred embodiments, those of ordinary skill in the art may, upon
reading this disclosure, appreciate changes and modifications which
may be made and which do not depart from the scope and spirit of
the invention as described above and claimed below.
* * * * *